This application seeks to renew the Alzheimer's Disease Research Center (ADRC) at the University of California, Irvine (UCI). Our overall objectives are to elucidate the factors that trigger the onset of AD and its conversion from the prodromal state of MCI, and to define the clinical and pathological features of AD. Our ultimate goal is to identify means to prevent, mitigate and eradicate this disorder. Towards this end, the UCI ADRC proposes four Cores and 3 Projects. The Administrative Core, directed by Dr. Carl Cotman and co- directed by Dr. Frank LaFerIa, will manage, guide and support the ADRC. The Clinical Core (Core 6), directed by Dr. Claudia Kawas, follows the standard cohort (controls, MCI and AD) and two unique human cohorts: (1) Down syndrome subjects, which represents the single largest cause of early-onset AD, and (2) individuals over 90 years, a particularly high incidence dementia group well-represented in the area for inclusion in an autopsy study. The Data Management and Statistics Core, directed by Dr. Dan Gillen, will manage ADRC data and support the Cores and ADRC investigators in standard and novel data analysis. The Neuropathology and Tissue Resources Core, co-directed by Dr. Ron Kim and David Cribbs, will collect postmortem and distribute brain tissues and body fluids from the clinical cohorts. The Core will also support investigator driven translational research with transgenic animal models, beta-amyloid peptides (AP) and conformation specific antibodies to A. The Education and Information Transfer Core, directed by Dr. Ruth Mulnard, will assist in subject recruiting and in education and information among ADRC investigators and the community. To support the overall goals of the ADRC and provide leadership in the field, the UCI ADRC proposes three Projects: 1) Neuroimaging of Hippocampal Subfields in Older Adults & MCI (Project Leader: Craig Stark, Ph.D.); (2) Astrocyte-related molecular mechanisms underlying altered neuronal plasticity in Down syndrome (Project Leader: Jorge Busciglio, Ph.D.) and (3) Neural stem cells to treat and model Alzheimer Disease (Project Leader and new investigator: Mathew Blurton-Jones, Ph.D.). These projects and Cores will interact extensively with other ADRC investigators to continue to build an exciting and productive research environment directed at elucidating the triggers, features and ultimately treatments for cognitive decline and development of AD.